Medicinal and veterinary drugs are only effective if they are able to reach their site of action in the body of the human or animal. There are a number of situations in which drug molecules cannot reach their site of action, preventing many potential drug candidates from being utilized. These situations include those where the drugs (1) are poorly soluble in the relevant physiological fluids, such as blood serum or digestive fluids, (2) are unstable due to the action of enzymes, extremes of pH, or other physiological conditions, (3) are unable to cross various barriers, such as epithelial, mucosal, or membranous barriers, (4) stimulate an undesired immune response, and/or (5) are excreted from the bloodstream via the kidneys.
Some specific drug delivery problems for which there is no general solution include (1) the lack of oral bioavailability of hydrophobic drugs, (2) the inability of injectable drugs intended for treatment of diseases or conditions of the brain or nervous system to reach their site of action due to poor solubility or an inability to cross the blood-brain barrier, (3) the inability of hydrophilic drugs in general to cross mucosal and epithelial barriers, such as the intestinal mucosa, and (4) the inability of hydrophilic drugs to access targets inside of cells because of an inability to cross cellular membranes. In addition, the delivery of hydrophilic drugs such as proteins, peptides, nucleic acids, and other macromolecules is hampered by the degradation of these molecules in intestinal fluids or blood serum as well as renal clearance and immunogenicity.
A number of approaches have resolved some of these issues in specific cases, but there is yet no general solution to the problems of drug delivery. Some examples of existing approaches for solving these problems include (1) solublization of hydrophobic drugs in micelles formed from surfactants in aqueous media (Wiedmann and Kamel, J. Pharm. Sci. 2002, 91, 1743; MacGregor, et al., Adv. Drug Deliv. Rev. 1997, 25, 33), (2) encapsulation of drugs in polymeric matrices in the nanometer to micrometer size range which may be biodegradable and may contain bioadhesive functional groups or ligands (WO 02/15877, WO 02/49676), (3) encapsulation of hydrophilic drugs in liposomes (Anderson, et al., Pharm. Res. 2001, 18, 316; WO 99/33940), which may also display bioadhesive functional groups or ligands, (4) conjugation of drugs to molecules that are substrates for active transport systems (Kramer, et al., J. Biol. Chem. 1994, 269, 10621; WO 01/09163; US 2002/0098999), and (5) chemical derivatization of protein drugs with hydrophilic polymers to protect them from degradation, immune recognition, or renal excretion (Belcheva, et al., Bioconjugate Chem. 1999, 10, 932; Zalipsky, Bioconjugate Chem. 1995, 6, 150; U.S. Pat. No. 4,002,531; U.S. Pat. No. 4,179,337). None of these approaches, however, offers a general solution for all cases of drug delivery problems.
One deficiency of the micellar, liposomal, and polymeric nanoparticulate systems is the inability to tightly control the size of the complexes (particle size). There is substantial evidence that particles of specific size in the nanometer size range (5-100 nm) are especially capable of traversing epithelial, mucosal, and membranous barriers (Florence, et al., J. Control. Rel. 2000, 65, 253; Desai, et al., Pharm. Res. 1996, 13, 1838; WO 99/65467). A technology able to generate perfectly or nearly monodisperse populations of particles with the ability to control particle size at will has the potential to enhance uptake and tightly control the pharmacokinetics of the drugs being delivered. Technologies for generating liposomes of small size are especially lacking, as are methods to load these vesicles, such that most or all of the drug is contained within the interior aqueous compartment, rather than in the extraliposomal solution.
A second deficiency of current drug delivery strategies is the inability of existing systems to incorporate all of the functions required for delivery into a single system. For example, micelles have been used to solublize hydrophobic drugs, but have no means to target the drug to the intestinal mucosa and enhance permeation of the barrier. Nanoparticulate systems can protect proteins from the low pH and proteolytic enzymes of the stomach, but have not been designed to then protect these proteins in blood serum or lymph. These systems can also contain bioadhesive groups or ligands, but there is no way to regulate the presentation of these moieties to control the timing of adhesive and binding interactions or transmembrane or intracellular transport.
A third deficiency, which applies specifically to the stabilization of proteins by hydrophilic polymers, is that existing methods require covalent attachment of the polymers, such as poly(ethyleneglycol) (PEG) or oligosaccharides, at defined locations that do not interfere with binding. Current technology requires development of expression systems capable of post-translational attachment of oligosaccharides at these sites, random chemical derivatization with PEG, which can decrease activity, or laborious chemical synthesis of proteins to allow synthetic polymers to be attached to desired residues (WO 02/19963, WO 02/20033). In order to avoid attaching hydrophilic polymers at locations that interfere with the biological activity of a protein, detailed knowledge of the 3-dimensional structure of that protein, including its interaction with its binding partners, is required.